The present invention relates to novel indolinone derivatives useful as pharmaceuticals, to processes for preparing the compounds, to intermediates useful in the preparation of the compounds, to pharmaceutical compositions comprising the compounds, and to the use of the compounds as pharmaceuticals.
WO 96/40116 disclose that certain pyrrole substituted 2-indolinone derivatives are receptor tyrosine kinase inhibitors useful in the treatment of conditions responsive to receptor tyrosine kinase inhibitors, for example proliferative disorders such as cancer. A preferred compound, disclosed on page 17, is 3-(2,3-dimethylpyrrol-5-yl)methylene]-2-indolinone, also known as SU5416. Unfortunately, this compound has been found to exhibit poor solubility in water and low bioavailability upon oral and intravenous administration.
WO 99/61422 discloses further pyrrole substituted 2-indolinone derivatives as receptor tyrosine kinase inhibitors. A preferred compound, disclosed as compound 5 on page 214, is 3-[2,4-dimethyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]propionic acid, also known as SU6668. This compound has been found to possess superior oral activity to SU5416, but has been reported to lack the ability of that compound to inhibit the receptor tyrosine kinase Flt-3 (Abstract 497, Anne-Marie O""Farrell et al., America Society of Hematology Meeting, Orlando, Fla., USA, Dec. 7-11, 2001). Flt-3 is an important target for a tyrosine kinase inhibitor, especially for the treatment of Acute Myeloid Leukemia (AML), because about 30% of AML patients have been found to possess mutant forms of Flt-3 which lead to constitutive tyrosine phosphorylation of Flt-3 (Levis et al., Blood, Aug. 1, 2001, Vol. 98. No. 3, pp 885-887).
WO 01/60814 discloses pyrrole substituted 2-indolinone derivatives bearing certain amido substituents directly attached to the pyrrole ring as receptor tyrosine kinase inhibitors.
WO 02/055517 discloses indolinones substituted with aryl substituents at the 4 position which exhibit protein kinase modulating ability.
WO 01/42243 discloses that certain compounds containing two or more pyrrole substituted 2-indolinone groups covalently linked together through the 3 position on each pyrrole by one or more linker groups are also useful as receptor tyrosine kinase inhibitors.
Nonetheless, in view of the severity of conditions responsive to receptor tyrosine kinase inhibitors and of the recent identification of specific kinase inhibitor targets, a need exists for new receptor tyrosine kinase inhibitors with diverse properties.
Pyrrole substituted 2-indolinone derivatives bearing certain carboxamidoethyl groups at the 4 position on pyrrole have now been found that are inhibitors of receptor tyrosine kinases with particularly desirable properties.
Accordingly, the present invention provides a compound of formula (I): 
in which:
(i) R1 represents a hydrogen atom or a (1-4C)alkyl group; and R2 represents a group of formula -A1-NR5R6 in which each of R5 and R6 independently represents a hydrogen atom or a (1-4C)alkyl group and A1 represents (CH2)m, (CH2)n-A2-(CH2)p or (CH2CH2O)qCH2CH2 in which m is an integer of from 2 to 10, each of n and p is an integer of from 1 to 6, A2 is CHxe2x95x90CH, phenylene, biphenylene, cyclohexylene or piperazinylene and q is 1, 2 or 3;
(ii) R1 and R2 together represent -A3-NR7-A4- in which each of A3 and A4 independently represents (CH2)r or (CH2CH2O)sCH2CH2 in which r is an integer of from 2 to 6, s is 1, 2 or 3, and R7 represents a hydrogen atom or a (1-4C)alkyl group;
(iii) R1 and R2 together with the nitrogen atom to which they are attached represent a piperidinyl group, which piperidinyl group bears a substituent of formula -A5-R8 at the 4 position, in which A5 represents (1-4C)alkylene and R8 represents piperidin-4-yl; or
(iv) R1 and R2 together with the nitrogen atom to which they are attached represent a pyrrolidinyl, piperidinyl or morpholino group; and
R3 and R4 each independently represents a hydrogen atom, a halogen atom, a (1-4C)alkyl group, a (1-4C)alkoxy group, a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C)alkyl group and a (1-4C)alkoxy group, a group of formula R9S(O)2NR10xe2x80x94, a group of formula R11N(R12)S(O)2xe2x80x94, a group of formula R13C(O)N(R14)xe2x80x94 or a group of formula R15N(R16)C(O)xe2x80x94 in which each of R9, R11, R16 and R15 independently represents a (1-4C)alkyl group or a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C)alkyl group and a (1-4C)alkoxy group, and each of R10, R12, R14 and R16 independently represents a hydrogen atom or a (1-4C)alkyl group;
or a pharmaceutically-acceptable salt thereof.
Compounds of formula (I) have been found to be potent and selective inhibitors of one or more of the receptor tyrosine kinases PDGFR (platelet-derived growth factor), c-Kit, VEGFR (vascular endothelial growth factor) and Flt-3 in whole cell assays.
The invention also provides compounds of formula (Ia): 
wherein R is hydrogen, methyl, or ethyl;
or a pharmaceutically-acceptable salt thereof.
The invention also provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
In addition, the invention provides a method of treating a condition responsive to a tyrosine kinase inhibitor, the method comprising administering to a patient in need of treatment an effective amount of a compound of the invention.
Further, the invention provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition responsive to a tyrosine kinase inhibitor.
The present invention provides novel pyrrole substituted 2-indoline derivatives which are substituted at the 4 position of the pyrrole ring with carboxamidoethyl substituents.
As used herein, the terms alkyl and alkylene refer to a branched or unbranched group. However, the names of specific groups, such as ethyl, ethylene, propyl, propylene, butyl or butylene, signify unbranched groups or radicals, unless indicated otherwise, such as prop-2-yl. Examples of alkyl groups are methyl, ethyl, propyl, prop-2-yl, and butyl. Examples of alkylene groups are methylene, ethylene, propylene and butylene.
The term halogen atom includes fluorine, chlorine and bromine.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
The term xe2x80x9ctreatmentxe2x80x9d as used herein refers to the treatment of a disease or medical condition in a patient, such as a mammal (particularly a human), and includes:
(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;
(b) ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient;
(c) suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or
(d) alleviating the symptoms of the disease or medical condition in a patient.
The term xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic acids.
Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1-hydroxy-2-naphthoic acid) and the like. Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, xinafoic, tartaric, citric, malic, maleic, succinic, and benzoic acids.
One preferred sub-group of compounds of formula (I) is that in which:
(i) R1 represents a hydrogen atom or a (1-4C)alkyl group; and R2 represents a group of formula -A1-NR5R6 in which each of R5 and R6 independently represents a hydrogen atom or a (1-4C)alkyl group and A1 represents (CH2)m, (CH2)n-A2-(CH2)p or (CH2CH2O)qCH2CH2 in which m is an integer of from 2 to 10, each of n and p is an integer of from 1 to 6, A2 is CHxe2x95x90CH, phenylene, biphenylene, cyclohexylene or piperazinylene and q is 1, 2 or 3;
(ii) R1 and R2 together represent -A3-NR7-A4- in which each of A3 and A4 independently represents (CH2)r or (CH2CH2O)sCH2CH2 in which r is an integer of from 2 to 6, s is 1, 2 or 3, and R7 represents a hydrogen atom or a (1-4C)alkyl group; or
(iii) R1 and R2 together with the nitrogen atom to which they are attached represent a piperidinyl group, which piperidinyl group bears a substituent of formula -A5-R8 at the 4 position, in which A5 represents (1-4C)alkylene and R8 represents piperidin-4-yl.
Compounds belonging to the above preferred sub-group have been found to exhibit good solubility in water and good absorption on oral administration.
In this sub-group of compounds, preferably
(i) R1 represents a hydrogen atom or a (1-4C)alkyl group; and R2 represents a group of formula -A1-NR5R6 in which each of R5 and R6 independently represents a hydrogen atom or a (1-4C)alkyl group and A1 represents (CH2)m, (CH2)n-A2-(CH2)p or (CH2CH2O)qCH2CH2 in which m is an integer of from 2 to 10, each of n and p is an integer of from 1 to 6, A2 is CHxe2x95x90CH, phenyl-1,3-ene, phenyl-1,4-ene, biphenyl-2,2xe2x80x2-ene, cyclohex-1,3-ylene or piperazin-1,4-ylene and q is 1, 2 or 3;
(ii) R1 and R2 together represent -A3-NR7-A4- in which each of A3 and A4 independently represents (CH2)r or (CH2CH2O)sCH2CH2 in which r is an integer of from 2 to 6, s is 1, 2 or 3, and R7 represents a hydrogen atom or a (1-4C)alkyl group; or
(iii) R1 and R2 together with the nitrogen atom to which they are attached represent a piperidinyl group, which piperidinyl group bears a substituent of formula -A5-R8 at the 4 position, in which A5 represents (1-4C)alkylene and R8 represents piperidin-4-yl.
Preferably
(i) R1 represents a methyl group; and R2 represents a group of formula -A1-NR5R6 in which R5 represents a hydrogen atom, R6 represents a methyl group and A1 represents (CH2)m, (CH2)n-A2-(CH2)p or (CH2CH2O)qCH2CH2 in which m is an integer of from 2 to 10, each of n and p is 1 or 2, A2 is CHxe2x95x90CH, phenyl-1,3-ene, phenyl-1,4-ene, biphenyl-2,2xe2x80x2-ene, cyclohex-1,3-ylene or piperazin-1,4-ylene and q is 1, 2 or 3;
(ii) R1 and R2 together represent -A3-NR7-A4- in which each of A3 and A4 independently represents (CH2)r or (CH2CH2O)sCH2CH2 in which r is an integer of from 2 to 6, s is 1 or 2, and R7 represents a hydrogen atom or a (1-4C)alkyl group; or
(iii) R1 and R2 together with the nitrogen atom to which they are attached represent a piperidinyl group, which piperidinyl group bears a substituent of formula -A5-R8 at the 4 position, in which A5 represents propylene and R8 represents piperidin-4-yl.
More preferably,
(i) R1 represents a methyl group; and R2 represents a group of formula -A1-NR5R6 in which R5 represents a hydrogen atom, R6 represents a methyl group and A1 represents (CH2)m, in which m is 2, 3, 4, 5, 6, 7, 8, 9 or 10; (CH2)n-A1-(CH2)p in which n and p are each 1 and A2 is CHxe2x95x90CH, phenyl-1,3-ene, phenyl-1,4-ene, biphenyl-2,2xe2x80x2-ene or cyclohex-1,3-ylene; (CH2)n-A2-(CH2)p in which n and p are each 2 and A2 is piperazin-1,4-ylene; or (CH2CH2O)qCH2CH2 in which q is 2 or 3;
(ii) R1 and R2 together represent xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94N(CH2CH3)xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)3xe2x80x94, or xe2x80x94(CH2CH2O)2CH2CH2xe2x80x94NHxe2x80x94(CH2CH2O)CH2CH2xe2x80x94; or
(iii) R1 and R2 together with the nitrogen atom to which they are attached represent a piperidinyl group, which piperidinyl group bears a substituent of formula -A5-R8 at the 4 position, in which A5 represents propylene and R8 represents piperidin-4-yl.
A particularly preferred sub-group of compounds is that in which R1 represents a methyl group and R2 represents a group of formula -A1-NR5R6 in which R5 represents a hydrogen atom, R6 represents a methyl group and A1 represents (CH2)m or CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2, in which m is an integer of from 2 to 6.
Compounds belonging to this sub-group have been found to exhibit particularly good potency as inhibitors of one or more of the above receptor tyrosine kinases.
Within this sub-group, preferably A1 represents (CH2)m or CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2, in which m is 2, 3 or 4.
More preferably A1 represents (CH2)2,(CH2)3 or CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2.
Especially preferred are compounds in which A1 represents (CH2)2.
Another preferred sub-group of compounds is that in which R1 and R2 together represent -A3-NR7-A4- in which each of A3 and A4 independently represents (CH2)r or (CH2CH2O)sCH2CH2 in which r is an integer of from 2 to 6, and s is 1, 2 or 3, and R7 represents a hydrogen atom or a (1-4C)alkyl group.
Compounds belonging to this sub-group have also been found to exhibit particularly good potency.
In this sub-group, preferably R1 and R2 together represent xe2x80x94(CH2)2xe2x80x94NR7xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94NR7xe2x80x94(CH2)3xe2x80x94, especially xe2x80x94(CH2)2xe2x80x94NR7xe2x80x94(CH2)2xe2x80x94.
Examples of particular values for R7 are hydrogen, methyl, ethyl, propyl, prop-2-yl and butyl.
Compounds in which R7 represents hydrogen are especially preferred.
Referring to R3 and R4, examples of particular values are:
hydrogen;
for a halogen atom: fluorine, chlorine or bromine, especially bromine;
for a (1-4C)alkyl group: methyl;
for a (1-4C)alkoxy group: methoxy;
for an unsubstituted or substituted phenyl group: phenyl;
for R8, R10, R12 and R14: methyl or phenyl;
for R9, R11, R13 and R15: hydrogen; and
for a group of formula R12C(O)N(R13)xe2x80x94: CH3C(O)NHxe2x80x94 and C6H5C(O)NHxe2x80x94.
Preferably R3 and R4 each independently represents a hydrogen atom, a bromine atom, CH3C(O)NHxe2x80x94, or C6H5C(O)NHxe2x80x94. More preferably R3 and R4 each independently represents a hydrogen atom.
Another preferred group of compounds of formula (I) are compounds in which:
(i) R1 represents a methyl group and R2 represents a group of formula -A1-NHCH3 in which A1 represents (CH2)m, CH2CHxe2x95x90CHCH2, CH2-phenylene-CH2, or CH2-cyclohexylene-CH2, in which m is an integer of from 2 to 8; or
(ii) R1 and R2 together represent xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94N(CH2CH3)xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)3xe2x80x94; and
R3 and R4 are each independently hydrogen.
Compounds of the above sub-group have been found to exhibit particularly good potency as inhibitors of one or more receptor tyrosine kinases. In particular, such compounds have demonstrated IC50 values for inhibition of the VEGFR tyrosine kinase of less than 1 xcexcM in the intracellular Ca2+ FLIPR or immunoprecipitation assay described below.
A more preferred sub-group of compounds within the above sub-group are compounds in which:
(i) R1 represents a methyl group and R2 represents a group of formula -A1-NHCH3 in which A1 represents (CH2)m, CH2CHxe2x95x90CHCH2, or CH2-(1,4-phenylene)-CH2 in which m is 2 or 3; or
(ii) R1 and R2 together represent xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)2xe2x80x94(CH2)2xe2x80x94N(CH2CH3)xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)3xe2x80x94.
Compounds belonging to this more preferred sub-group of compounds have demonstrated IC50 values for inhibition of both the VEGFR and PDGFR tyrosine kinases of less than 1 xcexcM in the intracellular Ca2+ FLIPR or immunoprecipitation assay described below.
A particularly preferred sub-group of compounds of formula (I) are compounds of formula (Ia): 
wherein R is hydrogen, methyl, or ethyl, and pharmaceutically-acceptable salts thereof.
Compounds of formula (Ia) that may be given special mention are:
3-[3,5-dimethyl-4-(3-oxo-3-piperazin-1-ylpropyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one and
3-[3,5-dimethyl-4-[3-oxo-3-(4-ethyl)piperazin-1-ylpropyl]-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one.
Especially preferred is the compound 3-[3,5-dimethyl-4-(3-oxo-3-piperazin-1-ylpropyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one, and pharmaceutically-acceptable salts thereof. This compound has been found to be a highly potent and selective inhibitor of PDGFR, c-Kit, VEGFR and Flt-3. It has also been found to have high solubility in water and to possess excellent absorption when administered orally to rats.
Another compound of formula (I) that may be given special mention is 3-[3,5-dimethyl-4-(3-oxo-3-homopiperazin-1-ylpropyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one.
The compounds of formula (I) are useful as receptor tyrosine kinase inhibitors for the treatment of proliferative disorders, such as forms of cancer which include, but are not limited to acute myeloid leukemia, small cell lung cancer, prostate cancer, gastrointestinal cancer, breast cancer and brain cancer, and other proliferative disorders, such as restenosis. The compounds may also be useful in restricting the growth of solid tumors.
According to another aspect, the present invention provides a process for the preparation of a compound of formula (I), which comprises
(a) reacting a compound of formula (II) 
or a reactive derivative thereof, with a compound of formula (III)
HNR1R2 xe2x80x83xe2x80x83(III) 
or a salt thereof, in which R1, R2, R3 and R4 are as defined hereinabove, or
(b) for a compound of formula (I) in which R5 or R7 represents a hydrogen atom, deprotecting a compound of formula (IV) 
in which R1a and R2a are as defined hereinabove for R1 and R2, except in that R5 or R7 is replaced with a group R5a or R7a respectively, in which R5a and R7a each represents an amine protecting group, and R3 and R4 are as defined hereinabove;
followed, if a pharmaceutically-acceptable salt is required, by forming pharmaceutically-acceptable salt.
In process (a), the reaction of a compound of formula (II) with a compound of formula (III) may conveniently be performed using a conventional amide coupling method. For example, an acid of formula (II) may be treated with a coupling agent, such as benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate (PyBOP) or o-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2Nxe2x80x2-tetramethyluronium hexafluorophosphate (HATU), in the presence of a base, such as N,N-diisopropylethylamine, and 1-hydroxy-7-azabenzotriazole (HOAt), followed by addition of the compound of formula (III). Convenient solvents include polar aprotic organic solvents, such as dimethylformamide. The temperature is conveniently in the range of from 0 to 50xc2x0 C. Alternatively, the compound of formula (II) may be converted into an acid halide, such as the chloride, and then reacted with the compound of formula (III).
In process (b), the amine protecting group represented by R5a or R7a may be a conventional amine protecting group. Examples of amine protecting groups are described in Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons, NY, 1991 and McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973. Examples of amine protecting groups include acyl groups, for example (1-6C)alkanoyl groups, such as acetyl; (1-6C)alkoxycarbonyl groups, such as t-butoxycarbonyl; and arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and arylmethyl groups, such as benzyl.
An acyl amine protecting group may conveniently be removed by treatment with an acid, such as trifluoroacetic acid.
Compounds of formula (II) are known, for example from WO 99/61422. They may also be prepared by reacting a compound of formula (VI) 
with a compound of formula (VII) 
The reaction is conveniently performed in the presence of a base, such as piperidine, in an organic solvent, such as ethanol, and under reflux.
Compounds of formula (VII) are known, for example from WO 99/61422.
Compounds of formula (VI) may be prepared by reacting a compound of formula (VIII) 
in which R8a represents a carboxyl protecting group, for example a (1-6C)alkyl group such as methyl, with phosphorus oxychloride and dimethylformamide, followed by removal of the protecting group R8a, for example by alkali hydrolysis.
Compounds of formula (VIII) may be prepared via the corresponding carboxylic acid (R8a is hydrogen) following methods as described in the accompanying examples.
Certain of the intermediates described herein are believed to be novel, for example the compounds of formula (IV). All such novel intermediates are provided as further aspects of the invention.
Pharmaceutical Compositions
When used as pharmaceuticals, the compounds of the invention will usually be administered in a pharmaceutical composition. The compositions comprise a compound of the invention as the active ingredient, together with a pharmaceutically-acceptable diluent or carrier. The compositions may be formulated for any route of administration, in particular for oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal administration. The compositions may be formulated in any conventional form, for example, as tablets, capsules, solutions, suspensions, dispersions, syrups, sprays, gels, suppositories, patches and emulsions.
The preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, the ingredients for such compositions are commercially available from, for example, Sigma (St. Louis, Mo.). By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams and White, Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams and White, Baltimore, Md. (1999).
According to another aspect, the present invention provides a pharmaceutical composition, which comprises a therapeutically-effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt thereof, together with a pharmaceutically-acceptable diluent or carrier.
In a preferred embodiment, the pharmaceutical compositions of the invention are suitable for oral administration. Suitable pharmaceutical compositions for oral administration may be in the form of capsules, tablet, pills, lozenges, cachets, dragees, powders, granules, or as a solution or suspension in a liquid, and the like; each containing a predetermined amount of a compound of the present invention as an active ingredient. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example polyvinylpyrrolidone. In addition, the active compound can be formulated in a controlled release dosage form as a tablet comprising a hydrophilic or hydrophobic matrix.
A composition in the form of a capsule can be prepared using routine encapsulation procedures, for example, by incorporation of active compound and excipients into a hard gelatin capsule. Alternatively, a semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into a hard gelatin capsule; or a solution of active compound in polyethylene glycol or a suspension in edible oil, can be prepared and filled into a soft gelatin capsule.
In another preferred embodiment, the compound of the invention can be formulated for injection, for example for intravenous injection. A typical composition for intravenous injection consists of a sterile isotonic aqueous solution containing, for example, active compound and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride. Other examples of suitable excipients include lactated Ringer""s injection, lactated Ringer""s plus dextrose injection, Normosol-M and dextrose, Isolyte E, acylated Ringer""s injection, and the like. Optionally, a co-solvent, for example, polyethylene glycol; a chelating agent, for example, ethylenediamine tetraacetic acid; a stabilizing agent, for example, a cyclodextrin; and an anti-oxidant, for example, sodium metabisulphite, may be included in the formulation.
According to another aspect, the present invention provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof for use in therapy.
The compounds of formula (I) are useful as receptor tyrosine kinase inhibitors. According to another aspect, therefore, the present invention provides the use of a compound of formula (I) or a pharmaceutically-acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition responsive to a tyrosine kinase inhibitor.
According to yet another aspect, the present invention provides a pharmaceutical composition for use in the treatment of a condition responsive to a tyrosine kinase inhibitor, which comprises a compound of formula (I) or a pharmaceutically-acceptable salt thereof.
The present invention also provides a method of treating a condition responsive to a tyrosine kinase inhibitor, which comprises administering to a patient in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt thereof.
The patient may be, for example, a mammal, such as a companion animal, and is preferably a human.
The dose (or effective amount) of the compound administered to a patient will depend upon many factors, including the particular compound used, the nature and severity of the condition being treated, the species of the patient, the weight of the patient and the route of administration. In general, a dose in the range of from 0.01 to 100 xcexcM/kg of bodyweight will be administered.
The following non-limiting examples illustrate representative pharmaceutical compositions of the invention.